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Enantioselective capillary electrophoresis for the assessment of CYP3A4-mediated ketamine demethylation and inhibition in vitro.
MedLine Citation:
PMID:  21983822     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Enantioselective CE with sulfated cyclodextrins as chiral selectors was used to determine the CYP3A4-catalyzed N-demethylation kinetics of ketamine to norketamine and its inhibition in the presence of ketoconazole in vitro. Ketamine, a chiral phencyclidine derivative, was incubated with recombinant human CYP3A4 from a baculovirus expression system as racemic mixture and as single enantiomer. Alkaline liquid/liquid extracts of the samples were analyzed with a pH 2.5 buffer comprising 50 mM Tris and phosphoric acid together with either multiple isomer sulfated β-cyclodextrin (10 mg/mL) or highly sulfated γ-cyclodextrin (2%, w/v). Data obtained in the absence of ketoconazole revealed that the N-demethylation occurred stereoselectively with Michaelis-Menten (incubation of racemic ketamine) and Hill (separate incubation of single enantiomers) kinetics. Data generated in the presence of ketoconazole as the inhibitor could best be fitted to a one-site competitive model and inhibition constants were calculated using the equation of Cheng and Prusoff. No stereoselective difference was observed, but inhibition constants for the incubation of racemic ketamine were found to be larger compared with those obtained with the incubation of single ketamine enantiomers.
Authors:
Hiu Ying Kwan; Wolfgang Thormann
Publication Detail:
Type:  Journal Article     Date:  2011-08-31
Journal Detail:
Title:  Electrophoresis     Volume:  32     ISSN:  1522-2683     ISO Abbreviation:  Electrophoresis     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8204476     Medline TA:  Electrophoresis     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  2738-45     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Affiliation:
Department of Clinical Pharmacology and Visceral Research, University of Bern, Bern, Switzerland.
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